Genetic variants of endothelial PAS domain protein 1 are associated with susceptibility to acute mountain sickness in individuals unaccustomed to high altitude: A nested case-control study

The endothelial PAS domain protein 1 (EPAS1) gene functions to sense the blood oxygen level by regulating the hypoxia-inducible transcription factor pathway, and single nucleotide polymorphisms (SNPs) of EPAS1 have been found to have a strong and positive selection in the adaptation of the native Tibetan highland population to high-altitude hypoxia. The aim of the present study was to investigate the effect of EPAS1 SNPs on the risk of acute mountain sickness (AMS) and the physiological responses to acute high-altitude hypoxia in lowland humans. Three tag SNPs (rs6756667, rs13419896 and rs4953354; minor allele frequency, >= 5%) were selected and genotyped in 603 unrelated Han Chinese men, who had traveled to Lhasa (a high-altitude hypoxia environment) by plane, using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method. The data showed that the EPAS1 rs6756667 wild-type GG homozygous genotype was associated with elevated AMS risk compared with the AA and AG genotypes (odds ratio, 1.815; 95% confidence interval, 1.233-2.666; P=0.0023) using the dominant-model analysis. EPAS1 rs6756667 GG genotypes were also associated with higher levels of hemoglobin, red blood cells and hematocrit than those carrying the AG heterozygote during AMS development. These findings indicate that EPAS1 SNPs play a role in the physiological effects of AMS, and these effects could be further evaluated as a therapeutic strategy to control acute hypoxia-related human diseases.